Process for preparing (1R,2S,4R)-(-)-2-[(2&#39;-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane and pharmaceutically acceptable acid addition salts thereof

ABSTRACT

A process for preparing (1R,2S,4R)-(−)-2-[(2′-[N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo [2.2.1]heptane and pharmaceutically acceptable acid addition salts thereof with higher yields and higher grades of purity.

The invention relates to a process for preparing(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneand pharmaceutically acceptable acid addition salts thereof.

The 2-(E)-butenedioate (1:1) salt (fumarate) of(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula

is a known anxiolytic active principle having the INN “deramciclanefumarate”.

The compound of Formula I falls under the general Formula I of Hungarianpatent No. 179,164 but has not been actually and explicitly disclosed inthis patent specification, nor the preparation thereof has beenexemplified. According to Hungarian patent No. 179,164 the alkanol aminecycloalkyl ethers of its general Formula I are prepared by reacting(+)-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one, i.e. (+)-camphor ofFormula

with the corresponding organic metal compound, subjecting the adductobtained to hydrolysis and introducing onto the is hydroxy group of theproduct obtained the basic side chain by etherification. As organicmetal compound a Grignard compound or an organic alkali metal compound,preferably lithium or sodium compound, is used.

The preparation of the compound of Formula I has been actually disclosedin Hungarian patent No. 212,574. The essence of this process is thatpurification of the product is carried out at a later stage of thesynthesis. According to the process (+)-camphor of Formula II issubjected to Grignard reaction with phenyl magnesium bromide in diethylether to give(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-olof Formula

with a yield of 28% (according to GC). The compound(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-olof Formula III is in the reaction mixture and is not isolated. Thecomplex is decomposed, the reaction mixture is converted withoutpurification into the sodium salt by reaction with sodium amide orsodium hydride and the sodium salt obtained is reacted with anhydrous(2-{chloro}-ethyl)-dimethylamine in toluene as medium. The reactionmixture contains beside the base(1R,2s,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I (being present in an amount of 20 to 30% a considerableamount of impurities and starting materials, e.g. unreacted (+)-camphorof Formula II,(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol,1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol and biphenyl, triphenylimpurities etc. The base(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[-phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I is separated from said contaminations by extraction withaqueous tartaric acid, whereupon the base is set free and the fumaratesalt is formed. The total amount of unreacted (+)-camphor of Formula IIand(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[(methyl]-bicyclo[2.2.1]heptane-2-olof Formula III remains in the organic phase of the tartaric acidextraction step, which can be re-used in the Grignard reaction afterremoving the solvent and water (i.e. it can be re-circulated into theprocess). Thus the (+)-camphor used can be more efficiently utilized;without re-circulation only about 16% by weight of the (+)-camphor usedcan be utilized, while in case of a one-fold and three-foldre-circulation this value is increased to 22% by weight and 25% byweight, respectively. Thus the yields are too low, particularly in theview of the commercial feasibility.

It is very important and is to be emphasized that a considerable part of(+)-camphor of Formula II used in the Grignard reaction does not reactand this starting material cannot be technically removed from thedesired product because of the physical properties of (+)-camphor andthe lability of the compound(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-olof Formula III formed since compound(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-olof Formula III is susceptible to decomposition. For this reasonaccording to the process disclosed in Hungarian patent No. 212,574 thealkylation step always takes place in the presence of (+)-camphor ofFormula II.

The aforesaid gives rise to the drawbacks of the process disclosed inHungarian patent No. 212,574. The alkali hydrides and amides used in thefirst step of the alkylation reaction form salts not only with thealcohol(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-olof Formula III but also with (+)-camphor of Formula II and othercompounds containing an active hydrogen atom being present in thereaction mixture. For this reason beside the desired compound(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I further alkylated derivatives formed, e.g. from unreacted(+)-camphor, are obtained and the desired compound(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I is to be recovered from a mixture containing suchimpurities and also unreacted compounds (+)-camphor and(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-olof Formulae II and III. The crude compound(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I can only be purified, though incompletely, by means ofrecrystallization from dimethyl formamide. However, with the aid of saidrecrystallization only non-basic contaminations can be completelyremoved, which do not form salts.

A further disadvantage of recrystallization from dimethyl formamide isthat the traces of the solvent cannot be removed from the desiredpharmaceutical active principle to the required extent.

It has been found that in case of the alkylation reaction of(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-olof formula III carried out with (2-{chloro}-ethyl)-dimethylamine(+)-camphor of Formula II being always present gives rise to theformation of considerable amounts of by-products, e.g.(1R,3S,4R)-3-[(2′-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-oneof Formula

The by-product(1R,3S,4R)-3-[(2′-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-oneof Formula V is formed as follows: under the conditions used in theetherification reaction (+)-camphor of Formula II forms an alkali saltin position 3 which in turn reacts with the(2-{chloro}-ethyl)-dimethylamine used as alkylating agent to yield thecompound of Formula V. The amount of the by-product of Formula V may beas high as 1 to 10% by weight. The solubility of the fumarate2-(E)-butenedioate (1:1) of the compound of(1R,3S,4R)-3-[(2′-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-oneof Formula V is approximately identical with that of the fumarate of thedesired compound(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I and therefore crystallizes together with the fumarate ofthe compound(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I and contaminates the desired end product. If theetherification is carried out in toluene, as described in Hungarianpatent No. 212,574, the product obtained after salt formation in ethanolcontains considerable amounts of the impurity(1R,3S,4R)-3-[(2′-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-oneof Formula V.

The salt is a highly unsoluble compound and can be recrystallized onlyfrom dimethyl formamide. However, recrystallization from dimethylformamide fails to provide a compound(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I in a purity required by the Pharmacopoeias for thefollowing reasons:

a) The product obtained after recrystallization from dimethyl formamidestill contains the compound(1R,3S,4R)-3-[(2′-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-oneof Formula V in an amount above the threshold value permitted byPharmacopoeia (about 0.5%);

b) Dimethyl formamide has a high boiling point and cannot be removedfrom the product in the required degree because at the high temperaturedecomposition of the product takes place.

A purification to yield products with a purity sufficient formedicaments according to the Pharmacopoeias could not be attained byusual purification processes, such as recrystallization from solvents orfractional distillation.

Taking into consideration the severe requirements of Pharmacopoeia,impurities being present in too high amounts may endanger the use of theactive principle for pharmaceutical purposes. The impurity(1R,3S,4R)-3-[(2′-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-oneof Formula V may therefore cause problems in the use of the compound(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.]heptaneof Formula I as active principle.

As a summary, it can be stated that when purifying the(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.]heptaneof Formula I prepared by the known method, dimethyl formamide would bethe only conceivable solvent. However, this recrystallization method isunsuitable for the preparation of a pharmaceutical active ingredientmeeting the requirements of the Pharmacopoeias, because dimethylformamide has such a high boiling point that traces thereof cannot beremoved from the product to a sufficient extent. At the high temperaturerequired the compound(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I is subject to decomposition.

As already disclosed above, (+)-camphor of Formula II is present duringthe alkylation reaction. From (+)-camphor as further contamination(1R,4R)-2-[(2′-{N,N-dimethyl-amino}-ethoxy)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula

is formed. If an alkali metal hydride or alkali metal amide is used asbasic salt forming agent, the amount of the contamination(1R,4R)-2-[(2′-{N,N-dimethylamino}-ethoxyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula IV is 1 to 10%. The compound(1R,4R)-2-[(2′-{N,N-dimethylamino}-ethoxy]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula IV has been known from the Prior Art [Yakugaku Zasshi, 75,1377, (1955); Chem., Abstr. 9340 (1956)]. The compound(1R,4R)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula IV is formed as follows:the alkali metal hydride or alkali metal amide used for sodium saltformation in the etherification step reduces 1 to 10% of (+)-camphor ofFormula II to borneol which is converted under the reaction conditionsused into the alkali metal salt and said alkali salt enters with(2-{chloro}-ethyl)-dimethylamine into an alkylation reaction. However,the borneol ether(1R,4R)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula IV can be separated from the desired compound(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I in the course of working up the reaction mixture.

The problem underlying to the invention is to provide a process forpreparing(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I and pharmaceutically acceptable acid addition salts thereofwith a higher grade of purity without the necessity of recrystallizationpurification steps which anyhow would lead only to an insufficientpurification and would reduce the yield and moreover would have thedrawback that the residual solvent could not be removed from the endproduct to a sufficient extent even by complicated methods.

Surprisingly the above has been solved by the present invention.

The present invention is based on the surprising recognition that if thereaction between the reaction mixture containing the compound(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-olof Formula III and (2-{chloro}-ethyl)-dimethylamine is carried out inthe presence of an alkali metal hydride or alkali metal amide in amedium containing 1 or more compound(s) having a 5- or 6-memberedsaturated heterocyclic ring with 2 oxygen ring atoms as [a] solvent(s),particularly dioxane, the reaction is directed by far in favour of theformation of the desired(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I and the by-product(1R,3S,4R)-3-[(2′-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-oneof Formula V is formed only in a minimal amount. The above recognitionenables the preparation of the desired compound(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I in higher yields and with a higher grade of purity,particularly considering the impurity(1R,3S,4R)-3-[(2′-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-oneof Formula V. Thereby a compound(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I which directly meets the requirements of Pharmacopoeia asregards the purity and the content of residual solvents can be obtained.

In the entire text the percentages regarding the contents of thecompounds of Formulae I an V and of other compounds are the result ofgas chromatographic analysis they being the ratio of the area under thegiven peak and the total area under all the peaks.

The term “pharmaceutically acceptable acid addition salts” used in thepresent patent specification means salts formed with inorganic acids,e.g. hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoricacid, or organic acids, e.g. acetic acid, tartaric acid, succinic acid,malic acid, lactic acid, citric acid, maleic acid or fumaric acid. Thesalt formed with fumaric acid possesses particularly useful properties.

The(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I has three asymmetrical centres, namely in positions 1, 2and 4.

Hence the subject matter of the invention is a process for preparing the(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I and pharmaceutically acceptable acid addition salts thereofby converting (+)-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one{(+)-camphor}of Formula

into(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-olof Formula

by reacting the former with a metallo-organic compound, if necessarycarrying out a decomposition, conveniently hydrolysis, of the reactionproduct, and reacting the(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-olof Formula III thus obtained with a (2-{halogeno}-ethyl)-dimethylaminein the presence of a basic salt forming agent in an organic solvent and,if desired, converting the base(1R,2S,4R)-(−)-2-[2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I thus obtained into a salt, characterised by carrying outthe reaction of(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-olof Formula III and (2-{halogeno}-ethyl)-dimethylamine in a mediumcontaining 1 or more compound(s) having a 5- or 6-membered saturatedheterocyclic ring with 2 oxygen ring atoms as [a] solvent(s). Theinvention is not limited to the use of 1 or more compound(s) having a 5-or 6-membered saturated heterocyclic ring with 2 oxygen ring atoms, suchas dioxane as the sole solvent(s) but also comprises the use of solventscontaining at least 50% by weight, preferably 75% by weight, of 1 ormore compound(s) having a 5- or 6-membered saturated heterocyclic ringwith 2 oxygen ring atoms, such as dioxane.

The essential feature of the process of the present invention is thatthe alkylation is carried out in a solvent which does not favour thealkylation reaction in position 3 of (+)-camphor of Formula II in thepresence of a basic salt forming agent. It has been found that compoundshaving a 5- or 6-membered saturated heterocyclic ring with 2 oxygen ringatoms, particularly dioxane, can be used advantageously for thispurpose.

Particularly preferably as a solvent dioxane is used. Another example isdioxolane.

Conveniently a phenyl magnesium halide is used as a metallo-organiccompound in a Grignard type reaction. Further examples are phenylalkalicompounds, such as phenyllithium.

Preferably phenyl magnesium bromide is used. Phenyl magnesium chloridecan also be used.

Suitably the process according to the invention may be carried out asfollows:

In the first step of the process of the present invention (+)-camphor ofFormula II is subjected to Grignard reaction with, for example, phenylmagnesium bromide. The reaction is carried out in a manner known per se.As reaction medium preferably tetrahydrofurane may be used. Phenylmagnesium bromide may be used in an amount of 1 to 3 moles, preferablyabout 1.5 mole, related to 1 mole of (+)-camphor of Formula II. One mayproceed preferably by preparing first the Grignard reagent frommagnesium and bromo benzene in the solvent used and thereafter addingthe solution of the (+)-camphor of Formula II in an organic solvent atthe boiling point of the reaction mixture. It is preferred to use thesame solvent for the preparation of the Grignard reagent and thedissolving of the (+)-camphor of Formula II. As a solvent advantageouslytetrahydrofurane may be used. Advantageously the reaction is carried outat the boiling point of the reaction mixture.

The reaction mixture is then cooled and the adduct obtained ishydrolysed. Hydrolysis may be carried out in a known manner, preferablyin acidic medium. It is preferred to use hydrochloric acid for thispurpose.

The(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-olof Formula III obtained after decomposition of the Grignard complex canbe subjected to alkylation without purifying the reaction mixturecontaining the same. The reaction can be carried out in the presence ofunreacted (+)-camphor of Formula II. However, this leads to theformation only of a minor amount of alkylated by-products becauseaccording to the process of the present invention the formation of(1R,3S,4R)-3-[(2′-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[(2.2.1]heptane-2-oneof Formula V is suppressed.

As already mentioned above, alkylation is carried out in a solvent whichdoes not favour the alkylation reaction in position 3 of (+)-camphor ofFormula II, i.e. in which (+)-camphor of Formula II is alkylated inposition 3 at most only to a very small extent. It is particularlypreferred to use dioxane as organic solvent because in a mediumcontaining dioxane the alkylation of (+)-camphor of Formula II takesplace at most only to a very small extent and consequently the amount ofthe undesired(1R,3S,4R)-3-[(2′-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-oneof Formula V in the end product(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I is low.

The asymmetrical centres of(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I in positions 1 and 4 are derived from the(+)-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one {(+)-camphor}ofFormula II.

The alkylation is carried out in the presence of a basic salt formingagent. The term “basic salt forming agent” means basic compounds whichconvert the hydroxy group into a salt. For this purpose advantageouslyalkali metal amides, e.g. sodium amide, or alkali metal hydrides, e.g.sodium hydride, may be used. It is preferred to use sodium amide.

Preferably as a (2-{halogeno}-ethyl)-dimethylamine(2-{chloro}-ethyl)-dimethylamine is used.

Suitably the basic salt forming agent is used in an amount of 1 to 3moles, preferably 1.5 to 2 moles, related to 1 mole of the(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-olof Formula III. The amount of the alkylating agent is advantageously 1.0to 2.5 moles, preferably 1 to 1.1 mole, related to the basic saltforming agent. Preferably the alkylation reaction of(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-olof Formula III with the (2-{halogeno}-ethyl)-dimethylamine is carriedout under heating, particularly at the boiling point of the reactionmixture. Suitably the reaction takes place within about 3 to 5 hours. Anadvantageous reaction time is about 4 hours.

The(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I may be converted into a pharmaceutically acceptable salt,preferably the fumarate, optionally without isolation of the former. Onemay preferably proceed as follows: from the reaction mixture obtainedafter alkylation the inorganic salts are removed by filtration at 0 to30° C., preferably at 20° C., whereupon the correspondingpharmaceutically acceptable acid, preferably fumaric acid, is added tothe filtrate in an approximately equimolar amount (1.0 to 1.5 mole). Thecrystalline product precipitated from the medium, such as the dioxanemedium, is filtered off.

Since the(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I or pharmaceutically acceptable acid addition salts thereof,particularly the(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptanefumarate (1:1) obtained by the process according to the inventioncontain[s] at most low amounts of(1R,3S,4R)-3-[(2′-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-oneof Formula V or of the pharmaceutically acceptable acid addition saltthereof, respectively, by the process according to the invention it canbe worked without recrystallization from dimethyl formamide anyhowleading only to insufficient purification used by known methods andconsequently without removal of traces of dimethyl formamide from thepharmaceutically active principle by methods unsuitable for the givenpurpose, too. Also this latter is a significant progress in view of theimpossibility to remove dimethyl formamide to the necessary extentbecause of its high boiling temperature at which(1R,2S,4R)-(−)-2-[2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I would be decomposed.

The invention includes a process for making compounds of the Formula I,and pharmaceutically acceptable acid addition salts thereof,characterized in that the compounds are essentially free of dimethylformamide. According to an embodiment of the invention, the compoundsmade by the process are completely free of dimethyl formamide. By being“essentially free” of dimethyl formamide, the presence of any minimalamount of dimethyl formamide, if it is present at all, does not limit orpreclude the use of the compounds for administration to a host.Compounds that meet Pharmacopoeia limits or U.S. Federal Food and DrugAdministration limits on the amount of dimethyl formamide in a compoundto be administered to a host are also “essentially free” of dimethylformamide. Compounds having 0.088% of dimethyl formamide or less byweight, or 880 ppm or less of dimethyl formamide, are also “essentially”free of dimethyl formamide.

The advantage of the process of the present invention is that it can becarried out with excellent yields and a highly pure product is obtained.Thus the yield of about 46% shown in the Examples is considerably higherthan the yields disclosed in the Prior Art which do not surpass 25% evenif (+)-camphor is re-circulated several times.

The invention is further illustrated by the following Examples. Themelting points given in the Examples are uncorrected values.

EXAMPLE 1(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptanefumarate (1:1) [Formula I] Grignard Reaction

To a suspension of 48.6 g (1.5 g atom) magnesium spans and 600 ml ofanhydrous tetrahydrofurane a 20 ml portion of a mixture of 236 g (1.5moles) of bromo benzene and 200 ml of anhydrous tetrahydrofurane isadded at the boiling point. Once the Grignard reaction has started, theresidual part of the bromo benzene mixture is added to the suspensiondropwise within an hour. The reaction mixture is heated to boiling untilthe magnesium is completely dissolved. To the Grignard compound asolution of 152.2 g (1.0 mole) of (+)-camphor of Formula II and 300 mlof anhydrous tetrahydrofurane is added under constant heating to boilingwithin about half an hour and the reaction mixture is heated to boilingfor a further period of 5 hours.

Hydrolysis

The reaction mixture is cooled to 25° C. and poured onto a mixture of500 ml of heptane, 400 g of ice, 30 g of sodium chloride and 150 ml ofconcentrated hydrochloric acid under stirring at 0° C. The organic phaseis separated and made alkaline to pH 10 by adding a 25% by weight/volumeaqueous ammonium hydroxide solution. After repeated separation thesolution is dried and evaporated in vacuo. Thus 220 g of a colourlessoil are obtained.

Analysis on the Basis of GC

The test is carried out on a Perkin Elmer Autosystem gas chromatograph.

Length 10 m (0.25 mm).

A 14% cyanopropyl 14% methyl polysiloxane fixed phase (CPSil-19CB,Chrompack [Handelsprodukt]) capillary column is used.

Injection is performed at 200° C.

Heating speed 10° C./minute.

Carrier gas: helium.

Detector: FID, injection temperature 200° C., final temperature 250° C.,gas pressure 40 kPa.

(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-olcontent: 66.5%

(+)-camphor content: 25%.

Etherification

To a suspension of 45.5 g (1.05 mole) sodium amide (content: 90% byweight/weight) and 500 ml of anhydrous dioxane a mixture of 220 g of thecolourless oil obtained by the hydrolysis containing(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol,and 100 ml of anhydrous dioxane is added at the boiling point withinhalf an hour. The mixture is heated to boiling for 2 hours, whereupon113.0 g (1.05 mole) of (2-{chloro}-ethyl)-dimethylamine are added andthe reaction mixture is heated to boiling for a further period of 4hours.

Formation of the Fumarate Salt

The suspension is cooled to 20° C., filtered, to the clear filtrate121.9 g (1.05 mole) of fumaric acid are added under vigorous stirring.The reaction mixture is heated to boiling for 10 minutes, cooled to 15°C., stirred for a further period of an hour and filtered. The filtercake is washed with dioxane, water and ethanol and dried at 80° C. untilfree of solvent. Thus 190.5 g (0.456 mole) of white crystals areobtained, yield 45.6% [based on (+)-camphor]. The melting point of thewhite crystals amounts to 214 to 216° C.

Analysis for the Formula C₂₀H_(3l)NO.C₄H₄O₄ (417.55)

calculated: C %=69.03%; H %=8.45%; N %=3.35%;

found: C %=69.06%; H %=8.42%; N %=3.39%.

[α]_(D) ²0=−92.5° (c=0.4, dimethyl sulfoxide, 435 nm).

The product contains less than 0.05% of(1R,3S,4R)-3-[(2′-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-onefumarate (1:1) contamination 100 g of the 2-(E)-butenedioate saltprepared as described above are stirred in 400 ml of anhydrous ethanolfor an hour at 60° C. The suspension is filtered at 10° C. and dried.Thus 97.5 g of the product are obtained. Yield 97.5%.

EXAMPLE 2 (Comparative Example)(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptanefumarate (1:1) [Formula 1] Reproduction of the process disclosed inHungarian patent No. 212,574 Grignard Reaction

To a Grignard compound prepared from 5.52 g (0.23 g atom) of magnesiumspans and 36.1 g (0.23 mole) of bromo benzene in 200 ml of anhydrousdiethyl ether a solution of 30.4 g (0.20 mole) of (+)-camphor and 50 mlof anhydrous diethyl ether is added. The reaction mixture is heated toboiling for 5 hours. The Grignard complex is decomposed by adding anicecold aqueous solution of 20 g of ammonium chloride, the mixture iswashed three times with 30 ml of water each, separated, dried overanhydrous magnesium sulfate and the solvent is removed by evaporation.Thus 40.5 g of a colourless oil are obtained which contains according toGC

57.5% of (+)-camphor of Formula II 5.8% of 1,7,7-tri-[methyl]-(borneol);34.5% of (1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol of Formula III; and 2.2% of furthercontaminations in smaller amounts.

Etherification

To a suspension of 3.4 g (67 millimoles) of sodium hydride (47.5% byweight/weight dispersion) and 50 ml of anhydrous toluene a solution of40.0 g of the oil obtained in the Grignard reaction containing(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-olof Formula III and 30 ml of anhydrous toluene are added. The reactionmixture is heated to boiling for an hour, whereupon a solution of 6.85 g(67 millimoles) of (2-{chloro}-ethyl)-dimethylamine and 10 ml of tolueneis added at the boiling point. The reaction mixture is heated to boilingfor a further period of 4 hours.

Separation

The reaction mixture is washed three times with 25 ml of water each. Theproduct is extracted with three equal portions of a solution of 18 g(0.12 mole) of tartaric acid and 40 ml of water. The phases areseparated, the aqueous layers are combined, made alkaline to pH 10 witha concentrated ammonium hydroxide solution, extracted three times with20 ml of dichloro ethane each, dried over magnesium sulfate and thesolvent is removed in vacuo. Thus 14.5 g of a colourless oil areobtained which contains according to GC analysis

74.2% of(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I;

16.5% of(1R,4R)-2-[(2′-{N,N-dimethylamino}-ethoxy]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula IV

6.5% of(1R,3S,4R)-3-[(2′-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-oneof Formula V; and some % of further unidentified contaminations each inan amount below 1%.

Formation of the Fumarate Salt

To a solution of 14.0 g of the base(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptaneof Formula I set free from the tartrate salt and 150 ml of ethanol 5.07g (43.6 millimol) of fumaric acid are added at 70° C. The product isfiltered at 0° C. and recrystallized from 50 ml of dimethyl formamide.

Thus 13.5 g of the desired product (1R,2S,4R)-(−)-2-[(2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptanefumarate (1:1) of Formula I are obtained in the form of white crystals.Yield 16.2% [based on (+)-camphor]. According to GC analysis in theproduct 0.5% of(1R,3S,4R)-3-[(2′-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-onecan be detected. Mp.: 214 to 216° C.

Analysis for the Formula C₂₀H₃₁NO.C₄H₄O₄ (417.55)

calculated: C %=69.03%; H %=8.45%; N %=3.35%;

found: C %=69.16%; H %=8.52%; N=3.32%.

What is claimed is:
 1. A process for preparing(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2,2,1]heptane of Formula

or a pharmaceutically acceptable acid addition salt thereof, whichcomprises converting (+)-1,7,7-tri-[methyl]-bicyclo[2,2,1]heptane-2-one{(+)-camphor} of Formula

into (1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo [2,2,1]heptane-2-ol of Formula

by reacting the former with a metallo-organic compound, if necessarycarrying out a decomposition of the reaction product, and reacting the(1 R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2,2,1]heptane-2-olof Formula III thus obtained with a (2-{halogeno}-ethyl)-dimethylaminein the presence of a basic salt forming agent in an organic solvent and,if desired, converting the base(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2,2,1]heptaneof Formula I thus obtained into a salt, wherein the reaction of(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2,2,1]heptane-2-olFormula III and (2-{halogeno}-ethyl)-dimethylamine is carried out in amedium containing 1 or more compounds [compound(s)] having a 5- or6-membered saturated heterocyclic ring with 2 oxygen ring atoms as asolvent.
 2. A process according to claim 1, wherein the reaction of(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2,2,1]heptane-2-olof Formula III and (2-{halogeno}-ethyl)-dimethylamine is carried out indioxane.
 3. A process according to claim 1, wherein a phenyl magnesiumhalide is used as the metallo-organic compound in a Grignard typereaction.
 4. A process according to claim 1, wherein the metallo-organiccompound is phenyl magnesium bromide.
 5. A process according to claim 1,wherein the metallo-organic compound is phenyl magnesium chloride.
 6. Aprocess according to claim 1, wherein the2-(2′-{halogeno}-ethyl)-dimethylamine is2-(2′-{chloro}-ethyl)-dimethylamine.
 7. A process according to claim 1,wherein the basic salt forming agent is sodium amide.
 8. A processaccording to claim 1, wherein the alkylation reaction of(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2,2,1]heptane-2-olof Formula III with the 2-(2′-halogeno}-ethyl)-dimethylamine is carriedout under heating.
 9. A process according to claim 1, wherein the base(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2,2,1]heptaneof Formula I is converted to the 2-(E)-butenedioate (1:1) salt(fumarate).
 10. A process according to claim 1, wherein the(1R,2S,4R)-(−)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2,2,1]heptaneof Formula I is converted into the 2-(E)-butenedioate (1:1) salt(fumarate) without isolation of the former.
 11. A process according toclaim 1, wherein the alkylation reaction of(1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2,2,1]heptane-2-olof Formula III with the 2-(2′-halogeno}-ethyl)-dimethylamine is carriedout at the boiling point of the reaction mixture.